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Several important application areas that will dominate systems, man, and cybernetic (SMC) efforts for at least the next decade, together with the methods that will require further research and development in order to appropriately address these application domains, are considered herein. More specifically, four broad and pervasive system domains are examined: service systems, infrastructure and transportation systems, environmental and energy systems, and defense and space systems. Given the nature of these four application domains, a number of new systems [i.e., holistic-oriented, including system-of-systems (SoS)], man (i.e., decision-oriented, including decision informatics), and cybernetic (i.e., adaptive-oriented, including real-time control) methods are identified and their further development are discussed. Clearly, the IEEE Society on Systems, Man, and Cybernetics has a great future; its systems, man, and cybernetic methods are relevant for addressing challenging problems arising in system domains that are becoming dominant in this 21st century. However, the methods must be refined and expanded to meet the changing needs of the 21st century; from a system to a system-of-systems vision, from a disciplinary to a multidisciplinary outlook, from a mass production to a mass customization focus, from a steady state to a real-time perspective, and from an optimal to an adaptive approach.